Posted by: Chris Cole | July 24, 2014

What a bleeding headache!!! Diagnostic dilemmas in suspected SAH in ED

While this topic could be said to almost rival thrombolysis of acute ischaemic stroke in the “Been Done To Death” stakes, I have nonetheless decided that it would be worthwhile to take a cook’s tour of the facts and evidence available around this contentious area of practice, and attempt to piece together what can at times be a seemingly disparate collection of apparently only loosely related jigsaw-like fragments, into some semblance of a unified, logical approach to the whole messy shebang.
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Or something like that.
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Firstly, a big shout out to Dr Archambeau and Dr Ghani for their recent insightful pieces on aspects of the same topic (links removed as they are to article on a private departmental website and not accessible to the great unwashed masses).
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While there will be some inevitable overlap, I’m mostly concerned with the specific issues surrounding the use of LP in diagnosing or excluding SAH, but if I tread on any toes, I offer my humblest apologies, and I promise I wasn’t setting out to create a demarcation dispute.
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Some background pathophysiology / epidemiology

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Around 1 in 40 adults have a cerebral circulation arterial aneurysm in their head:
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  • 90 % of these are saccular or “Berry” type aneurysms
  • 10 % are fusiform
  • Distribution is roughly  30% PCOM,  25% ACOM, and 20% MCA
 BrainAneurysms

Around 1 in 10 adults we see in ED with headache and investigate for SAH actually have a SAH.

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For folks with a SAH:

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  • 85 % are aneurysmal SAH
  • 10% are perimesencephalic SAH
  • 5 % are other random stuff (AVM, neoplasm, inflammatory, acute malignant HTN (cocaine, etc.))
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Perimesencephalic SAH is a very different beast to an aneurysmal SAH:
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  • Basically, they do well.
  • One study suggests 3% lifetime risk of re-bleed (what this means when the bleed causes no morbidity anyway is unclear).
  • One 22 year longitudinal follow-up study showed no difference in mortality or life expectancy between PMSAH patients and the general population (i.e. their ongoing risk of badness is the same as the background population risk).
  • Some groups suggest a repeat angiogram to “find the missed aneurysm” but there is no evidence to back this viewpoint.
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Imaging in suspected SAH

Vanilla CT

 There is much acrimony and disgruntlement about the varyingly quoted sensitivities of plain, non-contrast CT-brain for detecting or excluding SAH. Aline has covered this in some detail, so I’m not going to delve into it to any great depth. Suffice to say the major differences in opinion stem largely from 4 factors:
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  • Different generations of scanner have different diagnostic performance (i.e. newer / more-slices = better)
  • Your mileage varies depending on who you are scanning, and the inclusion/exclusion criteria varies somewhat between different (particularly older) studies. This is a function of variable pre-test probability.
  • Most studies use CSF analysis as the gold standard against which to judge CT. For reasons that will become apparent in but a few scrolls downwards, this is perhaps not the most well-founded of ideas.
  • For the borderline or subtle bleeds, the accuracy of the scan is highly dependent on who’s doing the reporting. There are several articles floating about from the Journal of the Blindingly Freaking Obvious (JBFO) demonstrating that experienced subspecialist neuroradiologists perform better than general radiologists, who perform better than emergency physicians (though, at the risk of being a bit parochial, we’re actually not that much worse) when diagnosing SAH on plain CT.
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With modern 64-slice or better plain CT, the numbers are none too shabby:
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Backes D et al. 2012 Stroke 2012;43(8):2115-9.
  • n = 137 with CSF spectrophotometry as the diagnostic gold standard
  • Sensitivity of plain CT < 12 hours = 98.5%
  • Captured all aneurysms + perimesencephalic bleeds but missed one AVM
  • Sensitivity > 6 hrs = 90%
  • Sensitivity < 6 hrs when only including those who presented with headache = 100%
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Perry J et al. 2011 BMJ 2011;343:d4277
  • n = 3,132 patients presenting to ED with sudden onset (< 1 hr) headache who had a CT
  • Sensitivity 92.9%, NPV 99.4% for all-comers irrespective of time of onset / delay to scan
  • n = 953 had their CT at < 6hrs post-onset of headache with n = 121 of them having SAH
  • Sensitivity/specificity/NPV/PPV = 100%
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CT with The Lot (CT Cerebral Angiogram)

You will all be familiar with the radiographer’s caveat of:  ”If it’s ok, we’ll leave the patient on the table until [Radiology Registrar de jour] has a look at the scan and decides if they want to do a CTA”. This is eminently sensible, as if the plain CT is positive for subarachnoid blood, it is a handy thing indeed to know where, and how big, that pesky aneurysm is. As noted above, however, 15% of the time we won’t find one, because they’re having a non-aneurysmal SAH (or the scan is a false positive, which is exceedingly rare, but does happen). But how good is CTA at finding aneurysms? As it turns out, pretty damn good:
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Li Q et al. 2013 Acta Radiol 2013 Sep 24 (Epub preprint)
  • n = 118 patients with a positive DSA (digital subtraction angiogram)
  • There were 145 aneurysms in those 118 patients
  • CTA found 96% of all aneurysms,  but found at least 1 aneurysm  in every one of the 118 patients
  • That is, no patients were missed
  • “Missed” aneurysms were small and non-contributory
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Lim LK et al. 2014 J Clin Neurosci 21(1);191-3.
  • n = 63 patients with SAH proven on CSF & DSA
  • NPV of CTA was 98%
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Zhang H et al. 2012 J Neuroimaging Dec 10 (Epub preprint)
  • n = 84 aneurysms in 71 patients
  • 64-slice CTA had sensitivity 97.6%, NPV 95.1%
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Wang H et al. 2013 Clin Radiol 2013;68(1)e15-20.
  • n = 54 aneurysms in 52 patients had 320-slice CTA + DSA
  • Sensitivity 96.3%, Specificity 100%

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Digital Subtraction Angiography (DSA)

This is essentially the imaging-based gold standard for finding aneurysms. Like most other good old-fashioned interventional angiographic procedures, however, it is not without its risks, and they are not negligible. This is very important to keep in mind when considering your choice of first and second line investigations for SAH, because a positive result on any of them will consign your patient to a DSA:
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Hankey GJ et al. 1990 Stroke 1990;21:209-222.
  • Risk of TIA/stroke 4%
  • Risk of permanent disabling CVA 1%
  • Mortality 0.06%
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LP and CSF analysis in suspected SAH

So, you suspect the guy who just rocked up to ED with his “worst headache everrrrr, dude!” of sudden onset might just have a SAH. (By the way, some 70-80% of non-frequent-flyer headaches seen in ED will describe this as their worst headache ever; that’s why they came to ED. It’s not a particularly good discriminator). You mutter to yourself a bit, bite the bullet and order a non-contrast CT-brain. Which looks normal to you. And to the radiology registrar/consultant. Bollocks. Being a good, medicolegally defensive, guideline-adherent emergency clinician, you decide to push on and do an LP, to fully exclude SAH. Because everybody knows that CSF analysis is the absolute rootin-tootin’, uber-reliable gold standard way to definitively find or exclude 100% of SAHs.
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Yep. And I have a bloody awesome collection of bridges to sell you. If you’d just step this way…
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There are currently THREE ways one can analyse CSF to determine whether the patient has any subarachnoid blood in their head:
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  1. Visual inspection for xanthochromia
  2. Spectrophotometric analysis for xanthochromia (i.e. measuring the extinction/absorption due to bilirubin in the CSF sample)
  3. Quantitative analysis of the ferritin concentration
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Visual inspection involves holding the CSF tube that you sent to the lab up to a white light, or against a well-lit sheet of white paper, turning to someone else in the lab and asking “Hey, Bill! Waddya reckon…. it is yellow… ish?”. Sadly, intrepid reader, this is not an exaggeration. I shit you not. This is exactly what our laboratory (and almost every clinical chemistry laboratory in Australia) currently does when we send them a CSF sample from a patient with suspected SAH. Which, to be fair, would be totally cool, if visual inspection for xanthochromia was a reliable test. But it is not:
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Marshman et al. 2014 Neurosurgery 74(4):395-9.
  • n = 26  mock CSF samples (clear stuff with known concentrations of bilirubin corresponding to range of values seen in real patients)
  • Clear samples misclassified 22% of the time
  • Yellow samples 29% of the time
  • 75% agreement in 46% of tests
  • 90% agreement in only 39% of tests
  • 88% of yellow specimens were called as clear
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Dupont et al. 2008 Mayo Clinic Proc. 2008; 82(12):1326-31.
  • n = 152, retrospective records trawling
  • Visual xanthochromia in 18/152 (12%)
  • Aneurysms in 13/18 (72%)
  • 1/18 (5.6%) patient had an aneurysm and negative visual xanthochromia
  • 5/18 (28%) had a DSA when they didn’t have an aneurysm because their CSF was visually “positive” for xanthochromia
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Arora et al. 2010 J Emerg Med. 2010;39(1):13-16.
  • n = 81 patients with headache suspicious for SAH
  • n = 19 with aneurysmal SAH
  • Sensitivity of visual inspection for SAH = 9/19 = 47%
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Linn et al. 2005 J Neurol Neurosurg Psychiatry 2005;76:1452-54.
  • n = 101 clinicans + students evaluating set concentrations of bilirubin
  • Arbitrary cut-off of 0.05 AU used to represent a “true positive”
  • Choice of cut-off was retrospective.
  • 100/101 got it right when bilirubin > 0.05 AU
  • 69% reported 0.02 AU as colourless
  • Post-hoc setting of cut-off to give the best looking results (dodgy as hell)
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Wallace AN et al. 2013 Stroke 44(6):1729-31.
  • n = 57 patients with negative CT, positive LP who then got DSA
  • Only 2 of them had aneurysms (3.5%)
  • Older review(s) suggest best case scenario 53% true positives
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Using visual inspection to detect xanthochromia has problems in both directions. It has poor sensitivity and poor specificity, thus leading to missed SAHs, as well as over-investigation (DSA), with its attendant risks, due to false positives. In terms of diagnostic performance as an assay, it represents the worst of both worlds. So why the hell do perfectly smart and usually sensible chemical pathologists choose to use visual inspection for xanthochromia as their official assay? Maybe the guidelines of their peak professional bodies recommend it? Actually, no:
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UK National Guildeines for analysis of CSF in suspected SAH
UK National External Quality Assessment Scheme for Immunochemistry Working Group
“…..Always use spectrophotometry in preference to visual inspection.”
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Beetham 2009 Scand Clin Lab Invest 2009; 69(1):1-7   Review article.
“…..Visual inspection of the CSF supernatant fluid for xanthochromia is insensitive and should not be used on any account.
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To be fair to the lab, there are valid reasons for not wanting to do it properly (and let’s face it, that’s what it comes down to; visual inspection is an inaccurate cop-out and spectrophotometry is demonstrably superior) which essentially amount to a combination of two factors:
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  1. Analytical interferences exist, caused by the overlapping absorption peaks of bilirubin and oxyhaemoglobin
  2. Deciding what method is best for compensating for that overlap, and choosing cut-offs and decision trees for most accurately reporting the clinical significance of the results obtained, given the clinical context of a suspected SAH, is tricky

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The first part is straightforward; the peak absorption wavelength of oxygenated Hb in the CSF (whether due to traumatic tap or native SAH) unfortunately sits very damn close to the absorption peak for bilirubin, our analyte of interest. The second bit is somewhat more problematic, and while I could bore you absolutely senseless with the details, the bottom line is that while it is a non-trivial problem, analytic methods and calculations have been developed which are extremely robust and quite straightforward to implement with existing standard equipment. Even I can understand them. If you’re truly excited or desperate enough, please check out the current UK Guidelines for an exhaustive explanation, replete with exhilarating spectral diagrams and colourful flowcharts:
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The TCH lab currently uses visual inspection for xanthochromia. The head of biochemistry has indicated he is amenable to (though far from enthusiastic about) developing and implementing a formal spectrophotometric method for CSF analysis to replace visual inspection. It is clear that this would only happen if ED clinicians really really want it, and even then the reporting flowchart/algorithm for determining what will be reported as “likely SAH / unlikely SAH / no freaking idea” will be largely up to ED (i.e. me) to develop. The official position is that biochemistry are aware that visual inspection sucks, and will start measuring it properly if pushed to it, but would rather not, as it will require a lot of fiddling to develop and adopt a robust methodology, and in conjunction with some ED clinicians (I may be the culprit here again) the biochemists optimistically wonder if we should be approaching the diagnosis of SAH in ED from a purely imaging-based perspective, anyway. (If anyone has an even bigger bee in their bonnet than I do about forcing the lab to adopt spectrophotometry for CSF analysis, let me know, but there is unlikely to be any significant action on it until the end of this year).
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Quantitative CSF ferritin measurement is the funky new kid on the block, and while it’s not quite ready for prime time, the only thing holding it back is the lack of a big-arsed prospective validation dataset. It is precise, easy to measure with standard equipment, and not plagued by the analytical interferences of CSF bilirubin. This will definitely be a “Watch This Space” contender to replace bilirubin/xanthochromia assays in the next few years.
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Petzold A et al. 2011 J Stroke Cerebrovasc Dis 20(6):488-93.
  • n = 14 (known SAH) + 44 controls (headache ?SAH & got LP)
  • Ferritin levels in controls 3.9 ng/mL for clean stabs and 9 ng/mL for traumatic taps
  • Ferritin levels in SAH = > 65ng/mL day 1 increasing to > 1,750ng/mL day 11
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Petzold A et al. 2009 Neurocrit Care 11(3):398-402.
  • n = 2 patients with CT +ve SAH
  • Serial measurements of CSF bilirubin and CSF ferritin
  • Bilirubin fell to “normal” by the end of 1-2 weeks
  • Ferritin peaked at ~3,000 ng/mL at 2 weeks (ref range < 12 ng/mL)
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Putting It All Together

So, someone wanders in to ED with a sudden onset thunderclap worst ever someone-just-dropped-an-axe-through-my-head sort of headache that started 2 hours ago, they have a GCS of 15 (NB: sunglasses don’t get you a score of 3 for eyes closed, and besides, if they’re the sort of person who comes to ED at night with a headache and wearing sunnies (pre-packed carpet bag, pillow and jim-jams are all optional extras) then they have no sinister intracranial pathology, anyway) and you find yourself wondering “Hey, I wonder if they have a SAH?”. You order a plain CT, and it’s normal. What to do now… ?
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Received wisdom whispers sternly in your ear: “LP… Do the Ell-Peee…”
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Cool. So you’re going to follow up a 98-100% sensitive test (plain CT) with an invasive, painful test, with the sensitivity/specificity of a coin-toss, because that’s the way we’ve always done it. What if there was another way?
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Mr EBM saunters up to your other shoulder, kicks Received Wisdom in the nether bits and provocatively suggests: “Use your braaaain, padawan… Use your braaaain.”
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If this patient has a SAH as the cause of their headache, we only care if it’s aneurysmal (85% of them, remember?). Because the 10% of them that are perimesencephalic are clinically irrelevant apart from needing to treat the headache with some analgesia, and the other 5% are caused by stuff that to a first approximation are simply unfixable. So if they have a suspicious headache, with a negative CT, would it make sense to look for an aneurysm, just in case? Let’s see what happens if we do a CTA, which has a NPV of ~98%. What happens if it’s positive? What if it’s negative?
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If the CTA is negative, the combined pre-test probability of ~10%, the negative predictive value of the plain CT of 95% (I’m being very pessimistic here), and the negative predictive value of the CTA of ~98% all comes out in the wash to produce a post-test probability of a missed aneurysmal SAH that is wayyy less than 1 in 10,000. I don’t know about you, but I’d be fairly comfortable discharging someone who I thought had a risk of 1 in 10,000 that their headache was a tiny SAH missed by both scans.
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If the CTA is positive, there are two options:
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  • The aneurysm is incidental (2.5% background chance) and a DSA is an unnecessary risk.
  • The aneurysm is the culprit (one of the 2% we may have missed on plain CT) and has bled but we can’t see the blood, and they should have a DSA and neurosurgical intervention as indicated.

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Those who are not terribly keen on the CT + CTA approach to excluding SAH are (quite reasonably) concerned about the first situation above: How many unnecessary / avoidable / extra DSAs will we end up doing because the CTA finds an incidental, “innocent” aneurysm? This is a valid concern, but a very quick consideration of the relative risks involved, informed by an understanding (often lacking) of just how bad CSF analysis for SAH is, can offer an informative perspective. Let’s crunch a few numbers:

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  • 100,000 patients present to ED with a suspicious headache, and cop a plain CT-brain
  • 9,800 have a positive CT and are appropriately shunted down the DSA / neurosurgical pathway
  • 90,200 have a negative CT (90,000 true negatives + the 200 that plain CT missed)
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Now we bifurcate and either give them a CTA, or an LP…..
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For the CTA crowd
  • 4,059 have a positive CTA (1804 innocent aneurysms + 2,255 culprit pathological aneurysms)
  • They all get a DSA:
    • 162 have a TIA/CVA but probably do okay at the end of the day. Probably.
    • 41 have a permanently disabling CVA and we’ve ruined their life.
    • 2 of them drop dead on the spot due to the DSA.
  • Number of unnecessary / extra DSA-harmed patients (due to CTA finding an innocent aneurysm)
    • 72 TIA/CVAs
    • 18 disabling CVAs
    • 1 death

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For the LP crowd
  • 3,517 have a positive LP
  • They all get a DSA:
    • 140 TIA/CVAs
    • 35 disabling CVAs
    • 2 deaths
  • Number of unnecessary / extra DSA-harmed patients (due to false positive LP)
    • 70 TIA/CVAs
    • 17 disabling CVAs
    • 1 death

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Within the margins of error involved with the figures employed, the number of patients harmed by “unnecessary” DSAs is the same, whether we choose a CTA or an LP as our second line investigation. What about the flip side of the coin:missing a real aneurysmal SAH?

For the CTA crowd

  • 90,200 CTAs performed
  • 170 of them have an aneurysmal bleed
  • 4 of them will have their lesion missed on CTA

For the LP crowd

  • 90,200 LPs performed
  • 170 of them have an aneurysmal bleed
  • 17 of them will have their lesion missed on LP*

(* NB: This is being very generous, as there is evidence the false negative rate can be considerably higher than 10%)

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SUMMARY

  • CT alone at < 6 hours post-ictus is probably enough. Honest. Certainly sufficient to drop the probability of badness to < 2%.
  • [ CT + LP ] and [ CT + CTA ] cause the same amount of harm from subsequent overinvestigation (DSA)
  • [ CT + LP ] misses at least 4 times as many real aneurysmal SAHs as [ CT + CTA ]
  • LP with visual inspection is a long long way from being a gold standard test for SAH
  • LP with spectrophotometry is much, much better but still not perfect
  • LP with ferritin measurement as the primary discriminator will be even better, but isn’t here yet
  • The other aspects of CTA (extra radiation, contrast load, having to convince a radiologist to do it) and LP (risk of infection, post-LP headache, extra diagnostic information to make or exclude alternative diagnoses) must be considered when deciding which approach to take, and may/will vary on a case by case basis, and between clinicians.
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